Processes for producing 5-fluorobenzoic acids and their intermediates

ABSTRACT

A process for producing a 5-fluorobenzoic acid of the formula (V), which comprises trichloromethylating a fluorobenzene of the formula (I) to obtain a 5-fluorobenzotrichloride of the formula (II), then reacting it with aqueous ammonia to obtain a 5-fluorobenzonitrile of the formula (III), reacting it with a fluorinating agent to obtain a 5-fluorobenzonitrile of the formula (IV) and hydrolyzing it: ##STR1## wherein each of X 1 , X 3 , Y 1  and Y 3  is a halogen atom, and each of X 2  and Y 2  is hydrogen or a halogen atom.

The present invention relates to processes for producing 5-fluorobenzoicacids useful as intermediates for medicines and their intermediatessafely and simply on an industrial scale.

Heretofore, a trichloromethyl group has been considered to be aprecursor for a carboxyl group. However, by the reaction of carbontetrachloride with e.g. p-fluorobenzene (J. Yurmi et al., Yiyao Gongye,16 (8), 370 (1985); CA, 104,50593 g) or o-difluorobenzene (JapaneseUnexamined Patent Publication No. 188643/1988), abisphenyldichloromethane is obtainable in good yield, and no substantialamount of benzotrichloride is obtainable.

However, 2,4-dichloro-5-fluorobenzotrichloride is obtainable bychlorinating 2,4-dichloro-5-fluorotoluene under irradiation withultraviolet rays (Japanese Unexamined Patent Publication No.74638/1983).

On the other hand, for the production of 2,4-dichloro-5-fluorobenzoicacid, it is known to employ a method of hydrolyzing2,4-dichloro-5-fluorobenzotrichloride (Japanese Unexamined PatentPublication No. 74638/1983), a method of acetylating1,3-dichloro-4-fluorobenzene, followed by haloformylation (EP 1760261(1986); DE 3435392 (1986); Japanese Unexamined Patent Publication No.85350/1986), or a method of reacting1-bromo-2,4-dichloro-5-fluorobenzene with magnesium to obtain a Grignardreagent, which is then reacted with carbon dioxide (Japanese UnexaminedPatent Publication No 237069/1985).

For the preparation of 2-chloro-4,5-difluorobenzoic acid, it is known toemploy a method of hydrolyzing 2-chloro-4,5-difluorobenzotrifluoride(Japanese Unexamined Patent Publication No.108839/1987), or a method ofacetylating 1-chloro-3,4-difluorobenzene, followed by haloformylation(Japanese Unexamined Patent Publication No. 45322/1989).

2-bromo-4,5-difluorobenzoic acid is obtained by hydrolyzing2-bromo-4,5-difluorobenzonitrile (I. Cervena et al., Collect Czech ChemCommun., 42,2001 (1977); CA. 87, 201469e)

For the preparation of 2,4,5-trifluorobenzoic acid, it is known toemploy a method of obtaining it at a low yield by the Balz-Schiemannreaction, or the Balz-Schiemann reaction and hydrolysis, of2-amino-4,5-difluorobenzoic acid (G.C. Finger et al., Illinois StateGeol. Survey Circ., 199,15 (1955)) or its ethyl ester (J. I. deGraw etat., J. Chem. Eng. Data, 13 (4), 587 (1968)), a method of reacting aGrignard reagent of 1-bromo-2,4,5-trifluorobenzene with carbon dioxide(Japanese Unexamined Patent Publications No. 160543/1983 and No.188839/1983), a method of cyanating 1-bromo-2,4,5-trifluorobenzene,followed by hydrolysis (Japanese Unexamined Patent Publication No.72885/1985; EP 191185 (1986)), a method of hydrolyzing a2,4,5-trifluorobenzoic acid halide, a method of hydrolyzing2,4,5-trifluorobenzotrifluoride (Japanese Unexamined Patent PublicationNo. 108839/1987) and a method of decarboxylating 3,4,6-trifluorophthalicacid (Japanese Unexamined Patent Publication No 52737/1989).

Further, for the preparation of 2,3,4-trichloro-5-fluorobenzoic acid, itis known to employ a method of nitrating 2,4-dichloro-5-fluorobenzoicacid to obtain 2,4-dichloro-5-fluoro-3-nitrobenzoic acid, followed byreduction and a Sandmeyer reaction (Japanese Unexamined PatentPublication No. 88157/1988).

As mentioned above, the conventional methods are not industriallyadvantageous involving irradiation with ultraviolet rays and thehaloformylation reaction, Grignard reaction and Sandmeyer reaction withlow batch efficiency and use of a diazonium salt or a hydrocyanic acidcompound harmful to human bodies, as well as problems relating to thequality of the material.

It is an object of the present invention to solve the above mentioneddrawbacks of the prior art.

The present invention provides a process for producing a 5-fluorobenzoicacid of the formula (V) useful as an intermediate for medicines and a5-fluorobenzotrichloride of the formula (II) as an intermediate thereof,and a 5-fluorobenzonitrile of the formula (III), safely and simply on anindustrial scale: ##STR2## wherein each of X₁, X₃, Y₁ and Y₃ is ahalogen atom, and each of X₂ and Y₂ is hydrogen or halogen atom.

The 5-fluorobenzoic acid of the formula (V) can be prepared by a processwhich comprises trichloromethylating a fluorobenzene of the formula (I)to obtain a 5-fluorobenzotrichloride of the formula (II), then reactingit with aqueous ammonia to obtain a 5-fluorobenzonitrile of the formula(III), reacting it with a fluorinating agent to obtain a5-fluorobenzonitrile of the formula (IV) and hydrolyzing it, or aprocess which comprises reacting a fluorobenzene of the formula (I) withcarbon tetrachloride in the presence of a Lewis acid catalyst to obtaina 5-fluorobenzotrichloride of the formula (II) and hydrolyzing it:##STR3## wherein each of X₁ and X₃ is a halogen atom, and X₂ is hydrogenor a halogen atom.

On the other hand, the 5-fluorobenzotrichloride of the formula (II) canbe obtained by reacting a fluorobenzene of the formula (I) with carbontetrachloride in the presence of a Lewis acid catalyst.

The 5-fluorobenzonitrile of the formula (III) can be prepared bytrichloromethylating a fluorobenzene of the formula (I) to obtain a5-fluorobenzotrichloride of the formula (II), and then reacting it withaqueous ammonia.

The trichloromethylation in the present invention is preferablyconducted by adding, preferably dropwise adding, the fluorobenzene ofthe formula (I) to carbon tetrachloride, preferably to an excess amountof carbon tetrachloride, in the presence of a Lewis acid catalyst, toconduct the reaction. In the present invention, the reaction of thefluorobenzene with carbon tetrachloride is preferably conducted undersuch a condition that a 5-fluorobenzotrichloride-Lewis acid complex ishardly formed as compared with a carbon tetrachloride-Lewis acidcomplex, whereby side reactions to formbis-(2,4-dihalogeno-5-fluorophenyl)dichloromethane orbis-(2,3,4-trihalogeno-5-fluorophenyl)dichloromethane can be suppressed,and the desired 5-fluorobenzotrichloride can be obtained in good yield.

The carbon tetrachloride is used usually in an amount of from 2 to 20moles, preferably from 4 to 10 moles, relative to one mole of thefluorobenzene such as 1,3-dihalogeno-4-fluorobenzene or1,2,3-trihalogeno-4-fluorobenzene. It is used as a reactant and as asolvent.

As the Lewis acid catalyst, aluminum chloride, aluminum bromide or analuminum chloride-sodium chloride (1:1) complex may be mentioned. Fromthe industrial point of view, aluminum chloride is preferred. It is usedusually in an amount of from 1 to 3 moles, preferably from 1.5 to 2.0moles per mole of the fluorobenzene.

The reaction temperature is usually from 10° to 80° C., preferably 60°to 80° C. The reaction time is usually from 10 to 60 minutes.

After completion of the reaction, usual post treatment and distillationare conducted to readily obtain the desired 5-fluorobenzotrichloridesuch as 2,4-dihalogeno-5-fluorobenzotrichloride or2,3,4-trihalogeno-5-fluorobenzotrichloride. A 5-fluorobenzonitrile canbe obtained by reacting the obtained 5-fluorobenzotrichloride withaqueous ammonia.

The concentration of the aqueous ammonia is preferably from 25 to 40%.It is used usually in an amount of from 10 to 40 moles, preferably from20 to 30 moles, per mole of the 5-fluorobenzotrichloride. The reactiontemperature is preferably from 90° to 120° C., and the reaction time ispreferably form 5 to 20 hours. After completion of the reaction, theammonia is recovered, and then the mixture is filtered. The filtrate isdistilled to obtain the desired 5-fluorobenzonitrile.

In the present invention, the fluorination of the 5-fluorobenzonitrileis preferably conducted in a solvent or in the absence of a solvent bymeans of an alkali metal fluoride such as KF, RbF or CsF. Particularlypreferred is KF.

A preferred solvent for the reaction is an aprotic polar solvent such asdimethylsulfoxide, dimethylformamide, sulfolane or N-methylpyrrolidone.The fluorination reaction may be conducted in the presence of a phasetransfer catalyst. Preferred phase transfer catalysts include ammoniumsalts or phosphonium salts such as tetramethyl ammonium chloride,tetrabutyl ammonium bromide, tetrabutylphosphonium bromide andtetraphenylphosphonium bromide.

In the 5-fluorobenzonitrile of the formula (III), when each of X₁ to X₃is Cl, Br or I, it will be substituted by fluorine, and each of Y₁ to Y₃in the corresponding formula (IV) will be F. In this case, thereactivity of X₁ to X₃ for fluorine substitution is X₃ >X₁ >X₂. Thereactivity of X₂ for fluorine substitution is higher in the case whereX₃ =X₁ =halogen atom other than F than the case where X₃ =X₁ =F. By thefluorine substitution reaction of X₁ to X₃, a mixture will be obtainedwhich comprises a compound wherein all of Y₁ to Y₃ are F and a compoundwherein a part of Y₁ to Y₃ is F.

As the alkali metal fluoride, KF is preferred. Particularly preferred isa material of fine particle form. KF is used usually in an amount offrom 1 to 4 molar excess, preferably from 1.2 to 2.5 molar excess,relative to the theoretical amount required for the reaction for mono-,di- or tri- substitution.

The solvent for reaction is used usually in an amount of from 1 to 10times preferably from 2 to 6 times, the weight of the compound of theformula (III). In a case where a phase transfer catalyst is employed,the amount is selected usually within a range of from 1 to 30 mol %,preferably from 5 to 15 mol %, relative to the material to befluorinated.

The optimum conditions such as the reaction temperature, time andpressute, may suitably be selected as the conditions for the mono-, di-or tri- substitution fluorination of the present invention. However,such fluorination is conducted usually within a temperature range offrom 100° to 220° C. for 1 to 20 hours under a pressure of from 0 to 1.0kg/cm². The compound of the formula (IV) such as2-chloro-4,5-difluorobenzonitrile or 2,4,5-trifluorobenzonitrileobtained by the fluorination of the compound of the formula (III) suchas 2,4-dichloro-5-fluorobenzonitrile, can be isolated by a usual methodfor separation such as filtration, distillation, etc.

The hydrolysis of the benzonitrile of the formula (IV) is usuallyconducted in a water-containing sulfuric acid. The optimum conditionsmay suitably be selected as the reaction conditions for the hydrolyticreaction of the present invention such as the sulfuric acidconcentration, the weight ratio with the benzonitrile, the reactiontemperature and time. However, the hydrolysis can usually be conductedat a concentration of from 50 to 70%, at a weight ratio of from 2 to 10,at a temperature of from 100° to 160° C. for a reaction time of from 1to 12 hours.

The 2-chloro-4,5-difluoro or 2,4,5-trifluorobenzoic acid obtained by thehydrolysis of the benzonitrile such as 2-chloro-4,5-difluoro or2,4,5-trifluorobenzonitrile, can usually be purified to a high purity byusual post-treatment.

The hydrolysis of the trichloromethyl product of the formula (II), isconducted in water-containing sulfuric acid. The optimum conditions maysuitably be selected as the reaction conditions for the hydrolyticreaction of the present invention, such as the sulfuric acidconcentration, the weight ratio with trichloromethyl product, thereaction temperature or time. However, the hydrolysis can be conductedusually at a concentration of from 85 to 95%, at a weight ratio of from1 to 4, at a temperature of from 30 to 100° C. for a reaction time offrom 1 to 5 hours.

The 2,4-dihalogeno-5-fluorobenzoic acid obtained by the hydrolysis ofthe 2,4-dihalogeno-5-fluorobenzotrichloride of the formula (II), or the2,3,4-trihalogeno-5-fluorobenzoic acid obtained by the hydrolysis of the2,3,4-trihalogeno-5-fluorobenzotrichloride of the formula (II), can beobtained in a high purity and in good yield by usual post-treatment andfiltration.

2,4-dichloro-5-fluorobenzonitrile and 2-chloro-4,5-difluorobenzonitrilein the compounds of the formula (III), and2-chloro-4,5-difluorobenzotrichloride and2,4,5-trifluorobenzotrichloride in the compounds of the formula (II),are novel substances identified for the first time by the presentinvention.

Now, the present invention will be described in further detail withreference to Examples. However, it should be understood that the presentinvention is by no means restricted by such specific Examples.

EXAMPLE 1

Into a 200 ml four-necked flask equipped with a stirrer, a refluxcondenser, a thermometer and a dropping funnel, 97 ml (1 mol) of carbontetrachloride and 33.3 g (0.25 mol) of aluminum chloride were charged,and 16.5 g (0.1 mol) of 1,3-dichloro-4-fluorobenzene was dropwise addedthereto at 75° C. Thereafter, the mixture was reacted for 10 minutes.After cooling, the reaction mixture was poured into 300 ml of ice water,and the organic layer was washed with a 5% sodium hydrogen carbonateaqueous solution. The organic layer thereby obtained was analyzed by gaschromatography and was found to be a carbon tetrachloride solutioncomprising a trichloromethyl product (70%) andbis(2,4-dichloro-5-fluorophenyl)dichloromethane (30%).

After distilling off carbon tetrachloride, the residue was cooled,whereby crystals precipitated partially. The crystals were removed byfiltration to obtain 21.3 g of crude oil. Then, this crude oil and 146 g(3 mol) of 35% aqueous ammonia were charged into a 500 ml pressurereactor and reacted at a temperature of from 103° to 106° C. for 12hours.

After completion of the reaction, ammonia was distilled off, and thecrystalline product was collected by filtration and washed with.10 ml ofchloroform. The filtrate and the chloroform washing solution weresubjected to liquid separation, and the aqueous layer was extracted withchloroform. The extract was put together with the separated organiclayer, followed by washing with water and drying. After distilling offchloroform, the residue was distilled under reduced pressure to obtain10.6 g (yield: 55.8%) of 2,4-dichloro-5-fluorobenzonitrile. Boilingpoint: 93°-95° C./1 mmHg; melting point: 43°-44° C.

This product was analyzed by the following analyses to identify thestructure.

IR analysis (KBr) (cm⁻¹); 3070, 2210, 1570, 1465.

NMR analysis <¹ Hnmr>δppm from TMS in CDCl₃ ; δ7.48 (1H, d, J=8.2 Hz);δ7.61 (1H, d, J=6.7 Hz).

Elementary analysis Analyzed value: Cl 37.3%; Calculated value as C₇ H₂Cl₂ FN: Cl 37.32%.

EXAMPLE 2

A mixture comprising 5.70 g (0.03 ) of2,4-dichloro-5-fluorobenzonitrile, 3.48 g (0.06 mol) of spray dried KFand 30 ml of dimethylsulfoxide, was reacted at a temperature of from140° to 150° C. for 3.5 hours in a glass reactor. After completion ofthe reaction, the mixture was poured into ice water (50 ml) andextracted with chloroform. The chloroform extract was washed five timeswith water and then dried. Then chloroform was distilled off. Theresidue was distilled under reduced pressure to obtain 3.57 g (yield:68.6%) of 2-chloro-4,5-difluorobenzonitrile. Boiling point: 105°-107°C./37 mmHg; melting point: 35°-37° C.

This product was analyzed by the following analyses to confirm itsstructure. IR analysis (KBr) (cm⁻¹); 3050, 2220, 1590, 1500.

MNR analysis <¹⁹ Fnmr>δppm from CFCl₃ in (CD₃)₂ CO; δ-125.7 ppm (d,d,d,J_(F-F) =20.6 Hz, J_(F-H) =9.9 Hz, J_(F-H) =7.9 Hz); δ-136.8 ppm (d,d,d,J_(F-F) =20.6 Hz, J_(F-H) =9.8 Hz, J_(F-H) =7.0 Hz); <¹ Hnmr>δppm fromTMS in (CD₃)₂ CO; δ7.78 ppm (1H,d,d, J_(F-H) =9.9 Hz, J_(F-H) =7.9 Hz);δ8.00 ppm (1H,d,d, J_(F-H) =9.8 Hz, J_(F-H) =7.9 Hz).

Elementary analysis Analyzed value: Cl 20.4%; Calculated value as C₇ H₂ClF₂ N: Cl 20.43%.

2.10 g of the 2-chloro-4,5-difluorobenzonitrile obtained as above and 12ml of 60% sulfuric acid were reacted under reflux for 10 hour. Aftercooling, the mixture was diluted with 20 ml of water and then extractedwith chloroform (10 ml×2 times). The extract was washed with water anddried, and then the solvent was distilled off to obtain 2.20 g (yield:94.8%) of 2-chloro-4,5-difluorobenzoic chloro-4,5-difluorobenzoic acid.Melting point: 103°-105° C.

EXAMPLE 3

A mixture comprising 9.50 g (0.05 mol) of2,4-dichloro-5-fluorobenzonitrile, 14.5 g (0.25 mol) of spray dried KFand 35 ml of dimethylsulfoxide, was reacted at a temperature of from160° to 165° C. for 5 hours in a glass reactor. After completion of thereaction, inorganic substances were collected by filtration and washedwith chloroform. The filtrate and the washing solution were poured intowater and extracted with chloroform. Then, the extract was washed withwater and dried. Then, chloroform was distilled off. The residue wasdistilled under reduced pressure to obtain 3.36 g (yield: 42.8%) of2,4,5-trifluorobenzonitrile. Boiling point: 94°-95° C./50 mmHg, n_(D) ²⁰1.473.

1.57 g of the 2,4-trifluorobenzonitrile obtained as above and 10 ml of60% sulfuric acid were refluxed for 9 hours. After cooling, the reactionmixture was poured into water and extracted with chloroform. The extractsolution was washed with water and dried. The solvent was distilled offto obtain 1.58 g (yield: 90%) of 2,4,5-trifluorobenzoic acid. Meltingpoint: 93°-95° C.

EXAMPLE 4

Into a 200 ml four-necked flask equipped with a stirrer, a refluxcondenser, a thermometer and a dropping funnel, 97 ml (1 mol) of carbontetrachloride and 26.7 g (0.2 mol) of aluminum chloride were charged,and 14.9 g (0.1 mol) of 1-chloro-3,4-difluorobenzene was graduallydropwise added over a period of 1.5 hours under reflux so thathydrochloride gas was slowly generated. The generated hydrochloride gaswas absorbed by an aqueous sodium hydroxide solution. After completionof the dropwise addition, the mixture was reacted for 10 minutes. Aftercooling to room temperature, the reaction mixture was poured into 300 mlof ice water. The organic layer was separated and washed with 100 ml ofwater, then with 100 ml of 5% of sodium hydrogen carbonate aqueoussolution and further with 100 ml of water. After distilling off carbontetrachloride, the residue was distilled under reduced pressure toobtain 17.4 g (yield: 65.4%) of 2-chloro-4,5-difluorobenzotrichloride.Boiling point: 104°-106° C./8 mmHg, n_(D) ²⁰ 1.540; purity: 98.2%

This product was analyzed by the following analyses to confirm itsstructure.

IR analysis (neat) (cm⁻ 1); 3060, 1601, 1485, 765 (CCl₃).

NMR analysis <¹⁹ Fnmr>δppm from CFCl₃ in (CD₃)₂ CO; δ132.5 ppm (d,d,d,J_(F-F) =20.6 Hz, J_(F-H) =11.9 Hz, J_(F-H) =20.6 Hz); δ137.5 ppm(d,d,d, J_(F-F) =20.6 Hz, J_(F-n) =11.9 Hz,

J_(F-H) =7.3 Hz); <¹ Hnmr>δppm from TMS in (CD₃)₂ CO; δ7.70 ppm (1H,d,d, J_(H-F) =9.9 Hz, J_(H-F) =7.3 Hz); δb 8.21 ppm (1H, d,d, J_(H-F)=11.9 Hz, J_(H-F) =8.1 Hz).

Elementary analysis Analyzed value: Cl 53.4%; Calculated value as C₇ H₂Cl₄ F₂ Cl 53.33%.

Then, into a 100 ml four-necked flask equipped with a stirrer, a refluxcondenser, a thermometer and a dropping funnel, 47 g of 95% sulfuricacid was charged, and 17.4 g of 2-chloro-4,5-difluorobenzotrichloridewas dropwise added thereto at a temperature of from 40° to 45° C.Hydrochloride gas generated was absorbed by an aqueous sodium hydroxidesolution. After reacting the mixture for one hour, the mixture waspoured into 300 ml of ice water, and precipitated crystals werecollected by filtration. The crystals were washed with a small amount ofcool water and dried to obtain 12.1 g (yield: 96%) of2-chloro-4,5-difluorobenzoic acid. Melting point: 103°-105° C.

EXAMPLE 5

The reaction and the post treatment were conducted in the same manner asin Example 4 except that 38.3 g of a pulverized product of a fusedmixture of aluminum chloride-sodium chloride (1:1) was used instead of26.7 g of aluminum chloride, to obtain 14.1 g of (yield: 53%) of2-chloro-4,5-difluorobenzotrichloride.

EXAMPLE 6

Into a 200 ml four-necked flask equipped with a stirrer, a refluxcondenser, a thermometer and a dropping funnel, 97 ml (1 mol) of carbontetrachloride and 26.7 g (0.2 mol) of aluminum chloride were charged,and 16.5 g (0.1 mol) of 1,3-dichloro-4-fluorobenzene was dropwised addedthereto under reflux. Thereafter, the mixture was reacted for 20minutes. Post treatment was conducted in the same manner as in Example 4to obtain 17.7 g (yield: 62.6%) of2.4-dichloro-5-fluorobenzotrichloride.

Boiling point: 94°-95° C./1mmHg; n_(D) ²⁰ 1.577; purity: 98.1%.

This product was analyzed was the following analyses to confirm itsstructure.

IR analysis (neat) (cm⁻¹); 3070, 1570, 1455, 767 (CCl₃).

NMR analysis <¹⁹ Fnmr>δppm from CFCl₃ in (CD₃)₂ CO; δ-115.5 ppm (d,d,J_(F-H) =10.3 Hz, J_(F-H) =6.8 Hz); <¹ Hnmr>δpm from TMS in (CD₃)₂ CO;δ7.58 ppm (1H, d, J=6.8 Hz); δ7.99 ppm (1H, d, H=10.3 Hz).

Elementary analysis Analyzed value: Cl 62.7% Calculated value as C₇ H₂Cl₅ F: Cl₆₂.78 %.

Then, in the same manner as in Example 4, 17.7 g of2,4-dichloro-5-fluorobenzotrichloride was dropwise added to 40 g of 95%sulfuric acid at 40° C. to conduct the hydrolysis, and treatment wasconducted in the same manner to obtain 12.7 g (yield: 97%) of2,4-dichloro-5-fluorobenzoic acid. Melting point 141°-142° C.

EXAMPLE 7

Into a 200 ml four-necked flask equipped with a stirrer, a refluxcondenser, a thermometer and a dropping funnel, 97 ml (1 mol) carbontetrachloride and 26.7 g (0.2 mol) of aluminum chloride were charged,and 13.2 g (0.1 mol) of 1,3,4-trifluorobenzene was dropwise addedthereto under reflux. Thereafter, the mixture was reacted for 20minutes. The reaction mixture was treated in the same as in Example 1 toobtain 7.49 g of (yield: 30%) of 2,4,5-trifluorobentrichloride.

Boiling point: 93°-95° C/1mmHg; n_(D) ²⁰ 1.506; purity: 98.3%.

This product was analysed by the following analyses to confirm itsstructure.

IR analysis (neat) (cm⁻¹); 3060, 1620, 1505, 767 (CCl₃).

NMR analysis <¹⁹ Fnmr>δppm from CFCl₃ in (CD₃)₂ CO; δ-115.5 ppm (d,d,d,J_(F-F) =20.6 Hz, J_(F-H) =10.8 Hz, J_(F-H) =6.7 Hz); δ-129.5 ppm(d,d,d,d, J_(F-F) =20.6 Hz, J_(F-F) =10.8 Hz, J_(F-H) =10.8 Hz, J_(F-H)=7.9 Hz); δ-141.7 ppm (d,d,d, J_(F-F) =20.6 Hz, J_(F-H) =10.8 Hz,J_(F-H) =7.9 Hz); <¹ Hnmr>δppm from TMS in (CD₃)₂ CO; δ7.49 ppm (1H,d,d,d, J_(H-F) =10.5 Hz, J_(H-F) =10.5 Hz, J_(H-F) =6.7 Hz); δ7.99 ppm(1H, d,d,d, J_(H-F) =10.8 Hz, J_(H-F) =7.9 Hz, J_(H-F) =7.9 Hz).

Elementary analysis Analyzed value: Cl 42.4%; Calculated value as C₇ H₂Cl₃ F₃ :Cl 42.64%.

Then, in the same manner as in Example 4, 7.46 g of2,4,5-trifluorobenzotrichloride was dropwise added to 30 g of 95%sulfuric acid at 40° C to conduct hydrolysis, and treatment wasconducted in the same manner to obtain 5.0 g (yield: 94.6%) of2,4,5-trifluorobenzoic acid. Melting point 95°-96° C.

EXAMPLE 8

Into a 200 ml four-necked flask equipped with a stirrer, a refluxcondenser, a thermometer and a dropping funnel, 97 ml (1 mol) of carbontetrachloride and 26.7 g (0.2 mol) of aluminum chloride were charged,and 19.3 g (0.1 mol) of 1-bromo-3,4-difluorobenzene was dropwise addedunder reflux. Thereafter, the mixture was reacted for 30 minutes. Thereaction mixture was treated in the same manner as in Example 1 toobtain 21.1 g (yield: 68.1%) of 2-bromo-4,5-difluorobenzotrichloride.

Boiling point: 96°-98° C./1 mmHg; n_(D) ²⁰ 1.563; purity: 98.6%.

This product was analysed by the following analyses to confirm itsstructure.

IR analysis (neat) (cm⁻¹) 3050, 1600, 1480, 760 (CCl₃).

NMR analysis <19Fnmr>δppm from CFCl₃ in (CD₃)₂ CO; δ-133.0 ppm (d,d,d,J_(F-F) =21.2 Hz, J_(F-H) =9.1 Hz, J_(F-H) =7.4 Hz); δ-136.9 ppm (d,d,d,J_(F-F) =21.6 Hz, J_(F-H) =11.4 Hz, J_(H-F) H=7.1 Hz); <1Hnmr>δppm fromTMS in (CD₃)₂ CO; δ7.90 ppm (1H, d,d, J_(H-F) =11.4 Hz, J_(H-F) =7.4Hz); δ8.27 ppm (1H, d,d, J_(H-F) =9.1 Hz, J_(H-F) =7.1 Hz).

Elementary analysis Analyzed value: Cl 34.3%; Calculated value as C₇ H₂BrCl₃ F₂ :Cl 34.27%.

Then, in the same manner as in Example 4, 17.5 g of2-bromo-4,5-difluorobenzotrichloride was dropwise added to 50 g of 95%sulfuric acid at 40° C., and the hydrolysis was conducted for two hoursand treatment was conducted in the same manner to obtain 12.6 g (yield:94%) of 2-bromo-4,5-difluorobenzoic acid. Melting point 110.5°-11.5° C.

EXAMPLE 9

Into a 200 ml four-necked flask equipped with a stirrer, a refluxcondenser, a thermometer and a dropping funnel, 97 ml (1 mol) of carbontetrachloride and 26.7 g (0.2 mol) of aluminum chloride were charged,and 20.0 g (0.1 mol) of 1,2,3-trichloro-4-fluorobenzene was dropwiseadded under reflux. Thereafter, the mixture was reacted for 30 minutes.The reaction mixture was treated in the same manner as in Example 1 toobtain 19.9 g (yield: 62.8%) of2,3,4-trichloro-5-fluorobenzotrichloride.

Melting point: 72°-73° C.; purity: 98.7%.

This product was analysed by the following analyses to confirm itsstructure.

IR analysis (neat) (cm⁻¹); 3060, 1590, 1470, 765 (CCl₃).

NMR analysis <¹⁹ Fnmr>δppm from CFCl₃ in (CD₃)₂ CO; δ-115.0 ppm (d,J_(F-H) =8.8 Hz); <1Hnmr>δppm from TMS in (CD₃)₂ CO; δ7.77 ppm (d,J_(H-F) =8.8Hz).

Elementary analysis Analyzed value: Cl 67.2%; Calculated value as C₇HCl₆ F: Cl 67.19%.

Then, in the same manner as in Example 4, 19.9 g of2,3,4-trichloro-5-fluorobenzotrichloride was dropwise added to 50 g of95% sulfuric acid at 40° C., and the hydrolysis was conducted for twohours and treatment was conducted in the same manner to obtain 14.5 g(yield: 95%) of 2,3,4-trichloro-5-trifluorobenzoic acid.

Melting point 150.0°-151° C.

As described in the foregoing, according to the present invention,fluorobenzonitriles, fluorobenzotrichlorides and fluorobenzoic acidsuseful as intermediates for medicines can be prepared safely and simplyon an industrial scale from fluorobenzenes.

We claim:
 1. A process for producing a 5-fluorobenzoic acid of theformula (V), which comprises trichloromethylating a fluorobenzene of theformula (I) to obtain a 5-fluorobenzotrichloride of the formula (II),then reacting it with aqueous ammonia to obtain a 5-fluorobenzonitrileof the formula (III), reacting it with a fluorinating agent to obtain a5-fluorobenzonitrile of the formula (IV) and hydrolyzing it: ##STR4##wherein each of X₁, X₃, Y₁ and Y₃ is a halogen atom, and each of X₂ andY₂ is hydrogen or a halogen atom, with the proviso that at least one ofX₁, X₂ and X₃ is a halogen atom other than fluorine, wherein said stepof reacting the compound of formula (III) with a fluorinating agentconverts at least one of said halogen atom other than fluorine tofluorine at the corresponding ring position of Y₁, Y₂ and Y₃.
 2. Aprocess for producing a 5-fluorobenzoic acid of the formula (VI), whichcomprises reacting a fluorobenzene of the formula (I) with carbontetrachloride in the presence of a Lewis acid catalyst to obtain a5-fluorobenzotrichloride of the formula (II), and hydrolyzing it:##STR5## wherein each of X₁ and X₃ is a halogen atom, and X₂ is hydrogenor a halogen atom.